An alleviative effect of Lonicerae japonicae flos water extract against liver fibrogenesis in vitro and in vivo.

Lonicerae japonicae (L. japonicae) flos is a medical and food homology herb. This study investigated the phenolic acid and flavonoid contents in L. japonicae flos water extract solution (LJWES) and the preventive effects of LJWES against liver fibrogenesis via FL83B cells and rats. LJWES contains many polyphenols, such as chlorogenic acid, morin, and epicatechin. LJWES increased cell viability and decreased cytotoxicity in thioacetamide (TAA)-treated FL83B cells (75 mM) (p < .05). LJWES decreased (p < .05) gene expressions of Tnf-α, Tnfr1, Bax, and cytochrome c but upregulated Bcl-2 and Bcl-xl in TAA-treated cells; meanwhile, increased protein levels of P53, cleaved caspase 3, and cleaved caspase 9 in TAA treated cells were downregulated (p < .05) by LJWES supplementation. In vivo, results indicated that TAA treatment increased serum liver damage indices (alanine aminotransferase [ALT] and alkaline phosphatase [ALP]) and cytokines (interleukin-6 and transforming growth factor-ß1) levels and impaired liver antioxidant capacities (increased thiobarbituric acid reactive substance value but decreased catalase/glutathione peroxidase activities) in rats (p < .05) while LJWES supplementation amended (p < .05) them. Liver fibrosis scores, collagen deposition, and alpha-smooth muscle actin deposition in TAA-treated rats were also decreased by LJWES supplementation (p < .05). To sum up, LJWES could be a potential hepatoprotective agent against liver fibrogenesis by enhancing antioxidant ability, downregulating inflammation in livers, and reducing apoptosis in hepatocytes.

Andrographolide Attenuates Oxidized LDL-Induced Activation of the NLRP3 Inflammasome in Bone Marrow-Derived Macrophages and Mitigates HFCCD-Induced Atherosclerosis in Mice.

Andrographolide (AND) is a bioactive component of the herb Andrographis paniculata and a well-known anti-inflammatory agent. Atherosclerosis is a chronic inflammatory disease of the vasculature, and oxidized LDL (oxLDL) is thought to contribute heavily to atherosclerosis-associated inflammation. The aim of this study was to investigate whether AND mitigates oxLDL-mediated foam cell formation and diet-induced atherosclerosis (in mice fed a high-fat, high-cholesterol, high-cholic acid [HFCCD] diet) and the underlying mechanisms involved. AND attenuated LPS/oxLDL-mediated foam cell formation, IL-1[Formula: see text] mRNA and protein (p37) expression, NLR family pyrin domain containing 3 (NLRP3) mRNA and protein expression, caspase-1 (p20) protein expression, and IL-1[Formula: see text] release in BMDMs. Treatment with oxLDL significantly induced protein and mRNA expression of CD36, lectin-like oxLDL receptor-1 (LOX-1), and scavenger receptor type A (SR-A), whereas pretreatment with AND significantly inhibited protein and mRNA expression of SR-A only. Treatment with oxLDL significantly induced ROS generation and Dil-oxLDL uptake; however, pretreatment with AND alleviated oxLDL-induced ROS generation and Dil-oxLDL uptake. HFCCD feeding significantly increased aortic lipid accumulation, ICAM-1 expression, and IL-1[Formula: see text] mRNA expression, as well as blood levels of glutamic pyruvic transaminase (GPT), total cholesterol, and LDL-C. AND co-administration mitigated aortic lipid accumulation, the protein expression of ICAM-1, mRNA expression of IL-1[Formula: see text] and ICAM-1, and blood levels of GPT. These results suggest that the working mechanisms by which AND mitigates atherosclerosis involve the inhibition of foam cell formation and NLRP3 inflammasome-dependent vascular inflammation as evidenced by decreased SR-A expression and IL-1[Formula: see text] release, respectively.

The psychological and physiological effects of integrated cognitive-behavioral and biofeedback therapy on panic disorder: A randomized controlled trial.

BACKGROUND: Cognitive-behavioral therapy (CBT) and biofeedback therapy are commonly regarded as effective treatment modalities for panic disorder. The aim of this study was to establish a Taiwanese version of an integrated cognitive-behavioral and biofeedback therapy (ICB) and examine its effects on panic disorder using psychological and physiological indicators. METHODS: Thirty patients with panic disorder were enrolled in this study. They were randomly assigned to either the ICB group (n = 15) or the treatment as usual (TAU) group (n = 15). The intervention consisted of six sessions, conducted once a week. Psychological indicators were measured at baseline (prior to intervention), week 3, and week 6, while physiological indicators were measured at baseline and week 6. The psychological indicators included five scales, with the Panic Disorder Severity Scale (PDSS) being the primary measure. The physiological indicators included respiratory sinus arrhythmia (RSA) and skin conductance, which respectively represent parasympathetic and sympathetic activity. RESULTS: Considering all participants, PDSS scores significantly decreased over time, but the difference between the ICB and TAU groups did not reach statistical significance. Among the physiological indicators, resting-state RSA and RSA under relaxation showed significant between-group differences over time, with the ICB group demonstrating a more pronounced improvement in RSA. CONCLUSION: In the context of existing pharmacological treatments, the benefits of ICB for panic disorder may not be observable through psychological indicators. However, it can lead to enhancement of parasympathetic activity as evidenced by the physiological indicators.

A traditional Chinese medicine formula NRICM101 to target COVID-19 through multiple pathways: A bedside-to-bench study.

COVID-19 is a global pandemic, with over 50 million confirmed cases and 1.2 million deaths as of November 11, 2020. No therapies or vaccines so far are recommended to treat or prevent the new coronavirus. A novel traditional Chinese medicine formula, Taiwan Chingguan Yihau (NRICM101), has been administered to patients with COVID-19 in Taiwan since April 2020. Its clinical outcomes and pharmacology have been evaluated. Among 33 patients with confirmed COVID-19 admitted in two medical centers, those (n = 12) who were older, sicker, with more co-existing conditions and showing no improvement after 21 days of hospitalization were given NRICM101. They achieved 3 consecutive negative results within a median of 9 days and reported no adverse events. Pharmacological assays demonstrated the effects of the formula in inhibiting the spike protein/ACE2 interaction, 3CL protease activity, viral plaque formation, and production of cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α. This bedside-to-bench study suggests that NRICM101 may disrupt disease progression through its antiviral and anti-inflammatory properties, offering promise as a multi-target agent for the prevention and treatment of COVID-19.

Preventive effects of folic acid on Zika virus-associated poor pregnancy outcomes in immunocompromised mice.

Zika virus (ZIKV) infection may lead to congenital microcephaly and pregnancy loss in pregnant women. In the context of pregnancy, folic acid (FA) supplementation may reduce the risk of abnormal pregnancy outcomes. Intriguingly, FA may have a beneficial effect on the adverse pregnancy outcomes associated with ZIKV infection. Here, we show that FA inhibits ZIKV replication in human umbilical vein endothelial cells (HUVECs) and a cell culture model of blood-placental barrier (BPB). The inhibitory effect of FA against ZIKV infection is associated with FRα-AMPK signaling. Furthermore, treatment with FA reduces pathological features in the placenta, number of fetal resorptions, and stillbirths in two mouse models of in utero ZIKV transmission. Mice with FA treatment showed lower viral burden and better prognostic profiles in the placenta including reduced inflammatory response, and enhanced integrity of BPB. Overall, our findings suggest the preventive role of FA supplementation in ZIKV-associated abnormal pregnancy and warrant nutritional surveillance to evaluate maternal FA status in areas with active ZIKV transmission.

Modulation effects of black-vinegar-based supplement against a high-fat dietary habit: antiobesity/hypolipidemic, antioxidative, and energy-metabolism effects.

BACKGROUND: An imbalanced fat or excess energy intake always results in obesity and increased serum/liver lipids, thus leading to metabolic syndromes. Given the bioactive components in black vinegar (BV), such as branched amino acids, phenolic profile, and mineral contents, we investigated the antiobesity effects of BV-based supplements in rats fed a high-fat diet (HFD). RESULTS: HFD (30% fat, w/w) feeding increased (P < 0.05) body weight, weight gains, weights of livers and mesenteric, epididymal, and perirenal adipose tissues, and serum/liver triglyceride levels relative to those of rats fed a normal diet (4% fat, w/w; CON). These increased values were ameliorated (P < 0.05) by supplementing with BV-based supplements but were still higher (P < 0.05) than those of CON rats. The increased areas of perirenal adipocytes in rats fed with an HFD were also decreased (P < 0.05) by supplementing with BV-based supplements, which might result from an upregulation (P < 0.05) of 5'-adenosine monophosphate-activated protein kinase (AMPK), carnitine palmitoyltransferase-1 (CPT1), and uncoupling protein-2 (UCP2) in the perirenal adipose tissues. A similar effect was observed for AMPK, peroxisome proliferator-activated receptor alpha, retinoid X receptor alpha, CPT1, and UCP2 gene and protein levels in livers (P < 0.05). Generally, BV-based supplements increased the fecal triglyceride, cholesterol, and bile acid levels of rats fed with an HFD, which partially contribute to the lipid-lowering effects. Furthermore, BV-based supplements increased (P < 0.05) hepatic Trolox equivalent antioxidant capacity and lowered (P < 0.05) serum/liver thiobarbituric acid reactive substances values in HFD-fed rats. CONCLUSION: In a chronic high-fat dietary habit, the food-grade BV-based supplement is a good daily choice to ameliorate obesity and its associated comorbidities. © 2020 Society of Chemical Industry.

Preventive effects of taurine against d-galactose-induced cognitive dysfunction and brain damage.

Oxidative stress arising from life processes or environmental influences and its resultant cellular dysfunctions are major causes of neurodegenerative disorders. The objectives of this study were to investigate whether taurine (Tau) can prevent d-galactose-induced cognitive dysfunction and brain oxidative damage. Mice given with Tau supplementation (100 and 400 mg per kg BW per day) spent shorter (p < 0.05) time in searching target in d-galactose (100 mg per kg BW per day) treated mice in a water maze reference memory experiment. Moreover, Tau supplementation extended (p < 0.05) the searching period around the target quadrant in the probe test of the water maze, and neuronal degeneration and nucleus shrinkage in the hippocampus dentate gyrus area of d-galactose treated mice were observed to be attenuated. Tau also downregulated (p < 0.05) expression of the glial fibrillary acidic protein (Gfap) and of the cluster of differentiation marker Cd11b; meanwhile, it strengthened (p < 0.05) antioxidant capacity and lowered (p < 0.05) the accumulation of advanced glycation end-products (AGEs) in the brain. Therefore, Tau could be effective to ameliorate oxidative damage and inflammation in the brain, and apoptosis of brain cells, which further lessen the cognitive dysfunction.

Effects of antrosterol from Antrodia camphorata submerged whole broth on lipid homeostasis, antioxidation, alcohol clearance, and anti-inflammation in livers of chronic-alcohol fed mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Antrodia camphorata is a functional fungus in Taiwan and owns several pharmacological functions. Antrosterol, a bioactive constitute of sterols in edible Antrodia camphorata submerged whole broth, can protect liver from CCl4 damage via enhancing antioxidant and anti-inflammatory capacities. AIM OF THE STUDY: The aim of this study was to investigate the hepatoprotection of antrosterol (named as EK100) against alcohol consumption. MATERIALS AND METHODS: A Lieber-DeCarli regular EtOH diet (EtOH liquid diet, 5% (v/v) alcohol) was applied to induce alcoholic liver damage. Mice were randomly divided into 5 groups: (1) Control: control liquid diet; (2) EtOH: EtOH liquid diet; (3) EK100_1X: EtOH liquid diet and 1mg EK100 (Antrosterol)/Kg body weight (bw); (4) EK100_5X: EtOH liquid diet and 5mg EK100/Kg bw; (5) EK100_10X: EtOH liquid diet and 10mg EK100/Kg bw. At the end of experiment, the livers were collected for histo-pathological analyses, RNA and protein extraction, and enzymatic activities. RESULTS: Antrosterol reduced serum/liver lipids of alcohol-diet fed mice which highly related to upregulated fatty acid ß-oxidation and downregulated lipogenesis, and increased fecal lipid/bile-acid outputs. Antrosterol enhanced hepatic antioxidant capabilities in alcohol-diet fed mice while it also lowered serum alcohol level, as well as increased alcohol dehydrogenase (ADH) and catalase (CAT) activities and decreased CYP2E1 protein expression in livers of alcohol-diet fed mice. Besides, antrosterol lowered hepatic inflammation and fibrosis related gene expressions, as well as serum AST/ALT values and TNF-α/IL-1ß contents in alcohol-diet fed mice. CONCLUSION: Based on the results, hepatoprotection of antrosterol is mostly attributed to its regulations of lipid homeostasis, antioxidant capability, alcohol metabolism, and anti-inflammation.

Preventive effects of Ophiocordyceps sinensis mycelium on the liver fibrosis induced by thioacetamide.

Thioacetamide (TAA), usually used as a fungicide to control the decay of citrus products, itself is not toxic to the liver, but its intermediates are able to increase oxidative stress in livers and further cause fibrosis. Ophiocordyceps sinensis mycelium (OSM) which contains 10% polysaccharides and 0.25% adenosine decreased (P < 0.05) the lipid accumulation and increased (P < 0.05) antioxidative capacity in livers of thioacetamide (TAA) injected rats. Meanwhile, the increased (P < 0.05) liver sizes, serum alanine transaminase (AST) and aspartate transaminase (ALT) values in thioacetamide (TAA)-injected rats were ameliorated (P < 0.05) by OSM supplementation. Moreover, the levels of proinflammatory cytokines, such as the tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), were also reduced (P < 0.05). The fibrosis phenomena in pathological (Masson's trichrome and H&E stainings) and immunohistochemical [α-smooth actin (αSMA) and CD86/ED1] observations in TAA-treated rats were reduced (P < 0.05) by OSM cotreatment. The protective effect of OSM against TAA-induced liver inflammation/fibrosis may be via downregulations (P < 0.05) of TGF-ß pathways and NFκB which further influenced (P < 0.05) the expressions of fibrotic and inflammatory genes (i. e., αSMA, Col1α, COX2). Therefore, OSM shows preventive effects on the development of TAA-induced hepatic fibrosis.

Pharmacological intervention for dengue virus infection.

Dengue virus (DENV) infection has a considerable health impact in tropical and subtropical countries worldwide. Escalation of infection rates greatly increases morbidity and mortality, most commonly from deaths due to dengue hemorrhagic fever and dengue shock syndrome. Although the development of an effective, long-lasting vaccine has been a major aim for control and prevention of DENV infection, the currently licensed vaccine has limitations and is less than satisfactory. Thus, there remains an important need to identify effective and tolerable medications for treatment of DENV-infected patients both in the early phase, to prevent progression to fatal outcomes, and to minimize deaths after patients develop severe complications. This review will address several specific points, including (1) approaches to identify anti-DENV medications, (2) recent advances in the development of potential compounds targeting DENV infection, (3) experience with clinical trials of regimens for DENV infection, (4) some available medications of potential for clinical trials against DENV infection, (5) reasons for unsuccessful outcomes and challenges of anti-DENV treatments, and (6) directions for developing or selecting better anti-DENV strategies. This review provides useful guidance for clinicians selecting drugs for DENV-infected patients with severe manifestations or potential fatal disease progression, and for basic researchers seeking to develop effective anti-DENV regimens.

Preclinical effects of honokiol on treating glioblastoma multiforme via G1 phase arrest and cell apoptosis.

BACKGROUND: Our previous study showed that honokiol, a bioactive polyphenol, can traverse the blood-brain barrier and kills neuroblastoma cells. PURPOSE: In this study, we further evaluated the preclinical effects of honokiol on development of malignant glioma and the possible mechanisms. METHODS: Effects of honokiol on viability, caspase activities, apoptosis, and cell cycle arrest in human glioma U87 MG or U373MG cells were assayed. As to the mechanisms, levels of inactive or phosphorylated (p) p53, p21, CDK6, CDK4, cyclin D1, and E2F1 were immunodetected. Pifithrin-α (PFN-α), a p53 inhibitor, was pretreated into the cells. Finally, our in vitro findings were confirmed using intracranial nude mice implanted with U87 MG cells. RESULTS: Exposure of human U87 MG glioma cells to honokiol decreased the cell viability. In parallel, honokiol induced activations of caspase-8, -9, and -3, apoptosis, and G1 cell cycle arrest. Treatment of U87 MG cells with honokiol increased p53 phosphorylation and p21 levels. Honokiol provoked signal-transducing downregulation of CDK6, CDK4, cyclin D1, phosphorylated (p)RB, and E2F1. Pretreatment of U87 MG cells with PFN-α significantly reversed honokiol-induced p53 phosphorylation and p21 augmentation. Honokiol-induced alterations in levels of CDK6, CDK4, cyclin D1, p-RB, and E2F1 were attenuated by PFN-α. Furthermore, honokiol could induce apoptotic insults to human U373MG glioma cells. In our in vivo model, administration of honokiol prolonged the survival rate of nude mice implanted with U87 MG cells and induced caspase-3 activation and chronological changes in p53, p21, CDK6, CDK4, cyclin D1, p-RB, and E2F1. CONCLUSIONS: Honokiol can repress human glioma growth by inducing apoptosis and cell cycle arrest in tumor cells though activating a p53/cyclin D1/CDK6/CDK4/E2F1-dependent pathway. Our results suggest the potential of honokiol in therapies for human malignant gliomas.

Comparing the metabolism of quercetin in rats, mice and gerbils.

PURPOSE: Several species of rodents are used to investigate the metabolism of quercetin in vivo. However, it is unclear whether they are a proper animal model. Thus, we compared the metabolism of quercetin in Wistar rats (rats), Balb/c mice (mice) and Mongolian gerbils (gerbils). METHODS: We determined the levels of quercetin metabolites, quercetin-3-glucuronide (Q3G), quercetin-3'-sulfate (Q3'S) and methyl-quercetin isorhamnetin (IH), in the plasma, lungs and livers of three species of animals by high-performance liquid chromatography after acute and/or chronic quercetin administration. The metabolic enzyme activities in the intestinal mucosal membrane and liver were also investigated. RESULTS: First, we found that after acute quercetin administration, the Q3'S level was the highest in gerbils. However, after long-term supplementation (20 weeks), Q3G was the dominant metabolite in the plasma, lungs and livers followed by IH and Q3'S in all animals, although the gerbils still had a higher Q3'S conversion ratio. The average concentrations of total quercetin concentration in the plasma of gerbils were the highest in both short- and long-term studies. The activities of uridine 5'-diphosphate-glucuronosyltransferase, phenolsulfotransferase and catechol-O-methyltransferase were induced by quercetin in a dose- and tissue-dependent manner in all animals. CONCLUSIONS: Taken together, in general, after long-term supplementation the metabolism of quercetin is similar in all animals and is comparable to that of humans. However, the accumulation of quercetin and Q3'S conversion ratio in gerbils are higher than those in the other animals.

Drynaria fortunei J. Sm. improves the bone mass of ovariectomized rats through osteocalcin-involved endochondral ossification.

AIM OF THIS STUDY: Our previous study showed that Drynaria fortunei J. Sm. (Kunze), a traditional Chinese medical herb, can promote osteoblast differentiation and maturation. This study was further aimed to confirm the traditional effects of Kunze on the bone mass of ovariectomized rats. MATERIALS AND METHODS: Female Wistar rats were given an ovariectomy and then administered the water extract of Kunze (WEK). Systemic and tissue toxicities of WEK were assessed. A biomechanical test, bone mineral contents, and bone histomorphometry were analyzed to determine the effects of the WEK on the bone mass. Levels of osteocalcin (OCN) in bone tissues were determined by immunohistochemistry and immunoblotting. The effects of naringin, one of the bioactive compounds of the WEK, on the bone mass were evaluated. RESULTS: A bilateral ovariectomy in rats caused a time-dependent decrease in levels of serum 17ß-estradiol. Exposure of ovariectomized rats to the WEK at 0.5 and 1g/kg body weight/day for 1, 2, 3, and 6 months did not induce systemic or tissue toxicities. Biomechanical testing and a bone mineral content analysis showed that the ovariectomy decreased the bone torsion force and bone ash in time-dependent manners. In comparison, after exposure to the WEK, the ovariectomy-induced reductions in the bone torsion force and bone ash were significantly alleviated. In parallel, results of a bone histomorphometric assay further revealed that the ovariectomy caused significant diminution in the production of prehypertrophic chondrocytes and trabecular bone but enhanced hypertrophic chondrocyte numbers in the growth plate. However, exposure to the WEK lowered ovariectomy-induced changes in these cellular events. As to the mechanism, the WEK increased OCN biosynthesis in bone tissues of ovariectomized rats. Administration of naringin to ovariectomized rats caused significant amelioration of the bone strength, bone mineral contents, and trabecular bone amounts. CONCLUSIONS: This study shows that the WEK can translationally promote the bone mass in ovariectomized rats through stimulating OCN-involved endochondral ossification.

Surfactant-modified nanoclay exhibits an antiviral activity with high potency and broad spectrum.

UNLABELLED: Nanomaterials have the characteristics associated with high surface-to-volume ratios and have been explored for their antiviral activity. Despite some success, cytotoxicity has been an issue in nanomaterial-based antiviral strategies. We previously developed a novel method to fully exfoliate montmorillonite clay to generate the most fundamental units of nanoscale silicate platelet (NSP). We further modified NSP by capping with various surfactants and found that the surfactant-modified NSP (NSQ) was less cytotoxic. In this study, we tested the antiviral potentials of a series of natural-clay-derived nanomaterials. Among the derivatives, NSP modified with anionic sodium dodecyl sulfate (NSQc), but not the pristine clay, unmodified NSP, a silver nanoparticle-NSP hybrid, NSP modified with cationic n-octadecanylamine hydrochloride salt, or NSP modified with nonionic Triton X-100, significantly suppressed the plaque-forming ability of Japanese encephalitis virus (JEV) at noncytotoxic concentrations. NSQc also blocked infection with dengue virus (DEN) and influenza A virus. Regarding the antiviral mechanism, NSQc interfered with viral binding through electrostatic interaction, since its antiviral activity can be neutralized by Polybrene, a cationic polymer. Furthermore, NSQc reduced the lethality of JEV and DEN infection in mouse challenge models. Thus, the surfactant-modified exfoliated nanoclay NSQc may be a novel nanomaterial with broad and potent antiviral activity. IMPORTANCE: Nanomaterials have being investigated as antimicrobial agents, yet their antiviral potential is overshadowed by their cytotoxicity. By using a novel method, we fully exfoliated montmorillonite clay to generate the most fundamental units of nanoscale silicate platelet (NSP). Here, we show that the surfactant-modified NSP (NSQ) is less cytotoxic and that NSQc (NSP modified with sodium dodecyl sulfate) could potently block infection by dengue virus (DEN), Japanese encephalitis virus (JEV), and influenza A virus at noncytotoxic concentrations. For the antiviral mechanism, we find that the electrostatic interaction between the negatively charged NSQc and the positively charged virus particles blocks viral binding. Furthermore, we used mouse challenge models of JEV and DEN to demonstrate the in vivo antiviral potential of NSQc. Thus, NSQc may function as a potent and safe antiviral nanohybrid against several viruses, and our success in synthesizing surfactant-modified NSP with antiviral activity may shed some light on future antiviral development.

Hepatoprotection of noni juice against chronic alcohol consumption: lipid homeostasis, antioxidation, alcohol clearance, and anti-inflammation.

Chronic alcohol consumption leads to steatohepatitis and cirrhosis. Naturally fermented noni juice (NJ) contains polyphenols, polysaccharides, and some trace minerals. This study explored protective effects of NJ against chronic alcohol consumption. Mice were assigned randomly to one of the following groups: (1) control, control liquid diet and distilled water; (2) alcohol, alcohol liquid diet and distilled water; (3) Alc+NJ_1X, alcohol liquid diet and 5 mL NJ/kg BW; (4) Alc+NJ_2X, alcohol liquid diet and 10 mL NJ/kg BW; (5) Alc+NJ_3X, alcohol and 15 mL NJ/kg BW for 4 weeks. NJ decreased (p < 0.05) serum AST, ALT, and alcohol levels and liver lipids, as well as increased (p < 0.05) daily fecal lipid outputs in alcohol-diet fed mice. NJ supplementation not only down-regulated (p < 0.05) lipogenesis but also up-regulated (p < 0.05) fatty acid ß-oxidation in livers of alcohol-diet fed mice. NJ also accelerated alcohol clearance via increased (p < 0.05) hepatic ADH and ALDH activities. NJ increased (p < 0.05) hepatic TEAC and GSH levels but decreased (p < 0.05) TBARS value and TLR2/4, P38, ERK 1/2, NFκB P65, iNOS, COX-2, TNF-α, and IL-1ß expressions in alcohol-diet fed mice. NJ promotes hepatoprotection against alcohol-induced injury due to regulations of lipid homeostasis, antioxidant status, alcohol metabolism, and anti-inflammatory responses.

Active Component of Danshen (Salvia miltiorrhiza Bunge), Tanshinone I, Attenuates Lung Tumorigenesis via Inhibitions of VEGF, Cyclin A, and Cyclin B Expressions.

Tanshinone I (T1) and tanshinone II (T2) are the major diterpenes isolated from Danshen (Salvia miltiorrhiza Bunge). Three human lung adenocarcinoma cell lines, A549, CL1-0, and CL1-5, were treated with T1 and T2 for the in vitro antitumor test. Results showed that T1 was more effective than T2 in inhibiting the growth of lung cancer cells via suppressing the expression of VEGF, Cyclin A, and Cyclin B proteins in a dose-dependent manner. Moreover, a transgenic mice model of the human vascular endothelial growth factor-A165 (hVEGF-A 165) gene-induced pulmonary tumor was further treated with T1 for the in vivo lung cancer therapy test. T1 significantly attenuated hVEGF-A165 overexpression to normal levels of the transgenic mice (Tg) that were pretreated with human monocytic leukemia THP-1 cell-derived conditioned medium (CM). It also suppressed the formation of lung adenocarcinoma tumors (16.7%) compared with two placebo groups (50% for Tg/Placebo and 83.3% for Tg/CM/Placebo; P < 0.01). This antitumor effect is likely to slow the progression of cells through the S and G2/M phases of the cell cycle. Blocking of the tumor-activated cell cycle pathway may be a critical mechanism for the observed antitumorigenic effects of T1 treatment on vasculogenesis and angiogenesis.

Beneficial effects of noni (Morinda citrifolia L.) juice on livers of high-fat dietary hamsters.

Polyphenols in noni juice (NJ) are mainly composed of phenolic acids, mainly gentisic, p-hydroxybenoic, and chlorogenic acids. To investigate the beneficial effects of NJ on the liver, hamsters were fed with two diets, normal-fat and high-fat diets. Furthermore, high-fat dietary hamsters were received distilled water, and 3, 6, and 9 mL NJ/kg BW, respectively. After a 6-week feeding period, the increased (p<0.05) sizes of liver and visceral fat in high-fat dietary hamsters compared to the control hamsters were ameliorated (p<0.05) by NJ supplementation. NJ also decreased (p<0.05) serum/liver lipids but enhanced (p<0.05) daily faecal lipid/bile acid outputs in the high-fat dietary hamsters. High-fat dietary hamsters supplemented with NJ had higher (p<0.05) liver antioxidant capacities but lowered (p<0.05) liver iNOS, COX-2, TNF-α, and IL-1ß expressions, gelatinolytic levels of MMP9, and serum ALT values compared to those without NJ. Hence, NJ protects liver against a high-fat dietary habit via regulations of antioxidative and anti-inflammatory responses.

Hypolipidemic and antioxidative effects of noni (Morinda citrifolia L.) juice on high- fat/cholesterol-dietary hamsters.

Noni juice (NJ) is rich in phytochemicals and polysaccharides. Lipid-lowering and antioxidative effects of NJ were investigated in this study. Fifty male hamsters were assigned randomly to one of the following groups: (1) normal diet and distilled water (LFCD); (2) high-fat/cholesterol diet and distilled water (HFCD); (3) HFCD and 3 ml NJ (including 0.20 g solids)/kg BW (NJ_L); (4) HFCD and 6 mL NJ (including 0.40 g solids)/kg BW (NJ_M); (5) HFCD and 9 ml NJ (including 0.60 g solids)/kg BW (NJ_H) for six weeks. NJ supplementation decreased (p < 0.05) serum triacylglycerol, cholesterol, atherogenic index, malondialdehyde levels, and hepatic lipids in HFCD hamsters, whereas serum trolox equivalent antioxidant capacity, glutathione, and fecal lipids in HFCD hamsters were increased (p < 0.05) by NJ supplementation. Although NJ supplementation downregulated (p < 0.05) sterol regulator element binding protein-1c in HFCD hamsters, it upregulated (p < 0.05) hepatic peroxisome proliferator-activated receptor-alpha and uncoupling protein 2 gene expressions in HFCD hamsters. Results demonstrate that NJ promotes cardioprotection in a high-fat/cholesterol diet.

Baicalein, isolated from Scutellaria baicalensis, protects against endothelin-1-induced pulmonary artery smooth muscle cell proliferation via inhibition of TRPC1 channel expression.

ETHNOPHARMACOLOGICAL RELEVANCE: We investigated the antiproliferative effects of baicalein, isolated from Scutellaria baicalensis (Huang-qin), on ET-1-mediated pulmonary artery smooth muscle cells (PASMCs) proliferation and the mechanisms underlying these effects. MATERIALS AND METHODS: Intrapulmonary artery smooth muscle cells were isolated and cultured from female Sprague-Dawley rats and used during passages 3-6. The proliferation of PASMCs was quantified by cell counting and XTT assay. The protein expression of TRPC1 and PKCα were determined by western blotting. The cell cycle pattern was assayed by flow cytometry. The intracellular calcium concentrations ([Ca(2+)](i)) were measured using the fluorescent indicator fura-2-AM and flow cytometry. RESULTS: Baicalein (0.3-3 µM) inhibited PASMCs proliferation, promoted cell cycle progression, enhanced [Ca(2+)](i) levels, increased capacitative Ca(2+) entry (CCE), upregulated the canonical transient receptor potential 1 (TRPC1) channel and membrane protein kinase Cα (PKCα) expression induced by ET-1 (0.1 µM). The PKC activator PMA (1 µM) reversed the inhibitory effects of baicalein on ET-1-induced upregulation of TRPC1 expression and S phase accumulation, while the PKC inhibitor chelerythrine (1 µM) potentiated baicalein-mediated G(2)/M phase arrest and TRPC1 channel inhibition. CONCLUSION: Our findings suggest that baicalein protects against ET-1-induced PASMCs proliferation via modulation of the PKC-mediated TRPC channel.

Baicalin, a flavonoid from Scutellaria baicalensis Georgi, activates large-conductance Ca2+-activated K+ channels via cyclic nucleotide-dependent protein kinases in mesenteric artery.

Baicalin isolated from Scutellaria baicalensis is a traditional Chinese herbal medicine used for cardiovascular dysfunction. The ionic mechanism of the vasorelaxant effects of baicalin remains unclear. We investigated whether baicalin relaxes mesenteric arteries (MAs) via large-conductance Ca2+-activated K+ (BK(Ca)) channel activation and voltage-dependent Ca2+ channel (VDCC) inhibition. The contractility of MA was determined by dual wire myograph. BK(Ca) channels and VDCCs were measured using whole-cell recordings in single myocytes, enzymatically dispersed from rat MAs. Baicalin (10-100 microM) attenuated 80 mM KCl-contracted MA in a concentration-related manner. L-NAME (30 microM) and indomethacin (10 microM) little affected baicalin (100 microM)-induced vasorelaxations. Contractions induced by iberiotoxin (IbTX, 0.1 microM), Bay K8644 (0.1 microM) or PMA (10 microM) were abolished by baicalin 100 microM. In MA myocytes, baicalin (0.3-30 microM) enhanced BK(Ca) channel activity in a concentration-dependent manner. Increased BK(Ca) currents were abolished by IbTX (0.1 microM). Baicalin-mediated (30 microM) BK(Ca) current activation was significantly attenuated by an adenylate cyclase inhibitor (SQ 22536, 10 microM), a soluble guanylate cyclase inhibitor (ODQ, 10 microM), competitive antagonists of cAMP and cGMP (Rp-cAMP, 100 microM and Rp-cGMP, 100 microM), and cAMP- and cGMP-dependent protein kinase inhibitors (KT5720, 0.3 microM and KT5823, 0.3 microM). Perfusate with PMA (0.1 microM) abolished baicalin-enhanced BK(Ca) currents. Additionally, baicalin (0.3-30 microM) reduced the amplitude of VDCC currents in a concentration-dependent manner and abolished VDCC activator Bay K8644-enhanced (0.1 microM) currents. Baicalin produced MA relaxation by activating BK(Ca) and inhibiting VDCC channels by endothelium-independent mechanisms and by stimulating the cGMP/PKG and cAMP/PKA pathways.